9-137710882-T-C

Variant names:

• chr9-137710882-T-C
• rs7039441
• NM_024757.5:c.22-85T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024757.5(EHMT1):​c.22-85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,475,878 control chromosomes in the GnomAD database, including 129,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13304 hom., cov: 32)
  • Exomes 𝑓: 0.41 (116673 hom.)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• Publications: 11 publications found

Genes affected

EHMT1 (HGNC:24650): (euchromatic histone lysine methyltransferase 1) The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

EHMT1 Gene-Disease associations (from GenCC):

• Kleefstra syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Kleefstra syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000283411 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-137710882-T-C is Benign according to our data. Variant chr9-137710882-T-C is described in ClinVar as Benign. ClinVar VariationId is 1292360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.22-85T>C		intron_variant	Intron 1 of 26	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.22-85T>C		intron_variant	Intron 1 of 26	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61777 AN: 151842 Hom.: 13293 Cov.: 32

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.407 AC: 539428 AN: 1323920 Hom.: 116673 AF XY: 0.414 AC XY: 270639 AN XY: 653778

African (AFR) AF: 0.433 AC: 13061 AN: 30160

American (AMR) AF: 0.311 AC: 10859 AN: 34962

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 9433 AN: 24372

East Asian (EAS) AF: 0.830 AC: 29144 AN: 35098

South Asian (SAS) AF: 0.620 AC: 47724 AN: 76996

European-Finnish (FIN) AF: 0.336 AC: 14613 AN: 43464

Middle Eastern (MID) AF: 0.489 AC: 2707 AN: 5538

European-Non Finnish (NFE) AF: 0.382 AC: 388657 AN: 1017816

Other (OTH) AF: 0.418 AC: 23230 AN: 55514

GnomAD4 genome AF: 0.407 AC: 61827 AN: 151958 Hom.: 13304 Cov.: 32 AF XY: 0.411 AC XY: 30526 AN XY: 74274

African (AFR) AF: 0.426 AC: 17670 AN: 41442

American (AMR) AF: 0.344 AC: 5253 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1360 AN: 3468

East Asian (EAS) AF: 0.813 AC: 4183 AN: 5142

South Asian (SAS) AF: 0.648 AC: 3121 AN: 4818

European-Finnish (FIN) AF: 0.317 AC: 3348 AN: 10562

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25606 AN: 67954

Other (OTH) AF: 0.403 AC: 846 AN: 2100

Alfa AF: 0.379 Hom.: 18428

Bravo AF: 0.404

Asia WGS AF: 0.723 AC: 2513 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.40
PhyloP100		-1.1
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7039441; hg19: chr9-140605334;